The effect of the oral administration of various antigens on the ocular immune response has been tested in the animal model for severe intraocular inflammatory disease, experimental autoimmune uveoretinitis, that is induced by both retinal S-antigen (S-Ag) and interphotoreceptor retinoid-binding protein (IRBP). Oral tolerance could be induced by repeatedly feeding S-Ag to rats. A putative suppresser cell that was CD8 positive could be isolated from the spleen of such animals and transferred to other animals to induce a similar tolerogenic effect. In addition, the role of the spleen was confirmed in ongoing animal experiments. A pilot study was performed in two patients that showed the induction of such tolerance, and these patients continue to be followed. A randomized masked trial to evaluate the usefulness of S-Ag feeding in patients with intraocular inflammatory diseases finished recruitment in August 1995, with publication of the trial in early 1997. The study was aimed to evaluate the effect and safety of the oral administration of retinal antigens on various parameters of ocular inflammation. It was a phase I/II randomized, masked trial. Patients with endogenous uveitis who were dependent on immunosuppressive agents were randomly assigned to receive either retinal S-antigen alone (n=10), retinal S-antigen and a mixture of soluble retinal antigens (n=10), retinal mixture of soluble antigens alone (n=10), or placebo (n-15). An attempt was then made to taper patients completely off their standard immunosuppressive therapy over an eight week period. The primary study endpoint was time to ocular inflammatory attack. The secondary study endpoint was the ability to taper patients completely off their immunosuppressive or cytotoxic medication within eight weeks. Time to development of uveitis was the main study endpoint and was not statistically significantly different for any of the four treatment groups. However, the group receiving the purified S-Antigen alone appeared to be tapered off their immunosuppressive medication more successfully as compared to placebo (p=0.08), while all the other groups appeared to do worse than those receiving placebo. No toxic effects attributable to any treatment were observed. This phase I/II study is the first to test the use of orally administered S-antigen in the treatment of uveitis. Although not statistically significant, patients given S-antigen were more likely to be tapered off their chronically administered systemic immunosuppressive therapy than the other groups tested.